Infection with the human herpes virus 8 (HHV8) has been linked to the occurrence of Kaposi's sarcoma (KS) and several lymphoproliferative disorders, such as primary effusion lymphoma (PEL), multi-centric Castleman's disease, angio-immunoblastic lymphadenopathy with dysproteinemia, and multiple myeloma. However, the exact mechanism of action of HHV8 in the pathogenesis of these disorders is still unclear. Although HHV8 has been found to encode homologs of several cellular oncogenes and growth factors, almost all of them lack expression in latently infected KS and PEL cells, thereby arguing against their casual role in the pathogenesis of these disorders. We have discovered that orf-K13, an HHV8-encoded vFLIP (viral FLICE inhibitory protein), is capable of blocking apoptosis induced by death receptors belonging to the Tumor Necrosis Factor Receptor (TNFR) family. More importantly, orf-K13 is capable of activating the NF-kappaB pathway, which has been previously implicated in the pathogenesis of EBV (Epstein Barr virus)- and HTLV1 (Human T cell Leukemia virus 1)- associated lymphoproliferative disorders. As orf-K13 is one of the few HHV8 encoded proteins which are expressed in latently infected KS and PEL cells, the above results make it an ideal candidate for causing the cellular transformation associated with infection by HHV8. The overall objective of this proposal is to test the above hypothesis using in vitro and in vivo models. In aim 1, biochemical and molecular characterization of the mechanisms underlying the NF-kappaB activating ability of orf-K13 will be carried out with the hope of identifying the interactions critical for this activity. In aim 2, biological consequences of orf-K13 mediated NF-kappaB will be studied and its effect on cellular activation, proliferation and transformation characterized. Aim 3 will focus on further characterization of the anti-apoptotic properties of orf-K13 and its biological consequences. In aim 4, transgenic approach will be used to study the in vivo role of orf-K13 in the pathogenesis of AIDS- related malignancies.